This is a U.S. National Phase Application Under 35 USC 371 and applicant herewith claims the benefit of priority of PCT/SE00/00357 filed Feb. 23, 2000, which was published under PCT Article 21(2) in English and Application No. 9900672-8 filed in Sweden on Feb. 25, 1999.
The present invention is related to a method whereby scar formation in the drainage fistula and subconjunctival bleb created during glaucoma surgery can be prevented. The invention is also related to a composition used for prevention of scar formation in the drainage fistula and subconjunctival bleb after glaucoma surgery.
Glaucoma is an eye disorder characterized by increased intraocular pressure, excavation of the optic nerve head, and gradual loss of visual field. An abnormally high intraocular pressure is commonly known to be detrimental to the eye, and there are clear indications that in glaucoma the intraocular pressure is the most important factor causing degenerative changes in the retina and the optic nerve head. The exact pathophysiological mechanism of open angle glaucoma is, however, still unknowns. Unless treated glaucoma may lead to blindness, the course of the disease typically being slow with progressive loss of vision.
The intraocular pressure is determined by the rate of production and drainage of aqueous humor in the anterior part of the eye. The aqueous humor is produced by the ciliary processes behind the iris. It then flows through the pupil into the anterior chamber, and normally exits the eye through the trabecular meshwork and Schlemm""s canal. However, in open angle glaucoma the resistance to outflow of aqueous humor is increased which causes the intraocular pressure to raise. The intraocular pressure in humans is normally around 12-21 mmHg. At higher pressures there is an increased risk that the eye may be damaged. In one particular form of glaucoma, namely low tension glaucoma, damage may, however, occur at intraocular pressures regarded to be within the normal physiological range. The opposite situation is also known i.e. some individuals may exhibit abnormally high intraocular pressure without any manifest defects in the visual field or optic nerve head. Such conditions usually are referred to as ocular hypertension.
Glaucoma treatment can be given by means of drugs, laser or surgery. Usually surgery is employed only when drug and laser treatments no longer are sufficiently effective. A relatively new medical treatment of glaucoma comprises the use of prostaglandins, which are administered topically on the eye, and reduce the intraocular pressure by enhancing the outflow of aqueous humor. Two such prostaglandin-based glaucoma drugs are currently being marketed in many countries, i.e. latanoprost (Xalatan(copyright)) and isopropyl unoprostone (Rescula(copyright)), and are extensively used clinically. The use of prostaglandins and derivatives is described in several patents and patent applications e.g. U.S. Pat No. 4,599,353 (Bito), U.S. Pat No. 4,952,581 (Bito), WO89/03384 (Sternschantz and Resul), WO 96/09055 (Sternschantz and Resul), EP 170258 (Cooper), EP 253094 (Goh) and EP 308135 (Ueno). In addition to these patents and patent applications a large number of new patent applications have been filed during the last years. Common for all these patents and patent applications is that they describe the use of prostaglandins for reduction of the intraocular pressure without surgery.
The prostaglandins are fatty acids usually derived from the precursors eicosatrienoic, eicosatetracnoic and eicosapentaenoic acid through metabolic steps involving oxygenation. Naturally occuring prostaglandins typically have the general structure presented below: 
The prostaglandins accordingly carry a cyclopentane ring to which two carbon chains attach, the upper chain usually being called the alpha chain and the lower chain usually being called the omega chain. The prostaglandins are classified in subgroups A, B, C, D, E, F, G, H, I, and J, depending on the structure and the substituents in the cyclopentane ring. The prostaglandins of particular interest in the present invention belong to the subgroups A and J, and their cyclopentane ring configuration is presented below: 
The alpha chain is a 7 carbon carboxy-terminated aliphatic chain whereas the omega chain is an 8 carbon methyl-terminated aliphatic chain. Depending on the number of double bonds in these chains, subscripts of 1 to 3 are given. In prostaglandins with subscript 1, e.g. PGA1, the double bond is situated between carbons 13 and 14 in the omega chain. In prostaglandins with subscript 2,e.g. PGJ2, an additional double bond is situated between carbons 5 and 6 in the alpha chain, and finally in prostaglandins with subscript 3, a third double bond is situated between carbons 17 and 18 in the omega chain. All naturally occuring prostaglandins furthermore carry a hydroxyl group on carbon 15.
Many different techniques have been described for glaucoma surgery. However, all techniques aim at creating a small drainage fistula for the aqueous humor to exit the eye in the vicinity of the trabecular meshwork. Thus the aqueous humor can bypass the trabecular meshwork tissue at Schlemm""s canal that usually is clogged in open angle glaucoma. The fluid is directed into a filtration bleb beneath the conjunctiva outside the eye. The most commonly practiced operation technique is called trabeculectomy and usually results in satisfactory pressure lowering of the eye. A very common complication, however, is formation of scar tissue in the filtration bleb, which reduces the drainage capacity of the filtration system created by surgery. The scar formation is mainly due to the proliferation and increased activity of fibroblasts. Consequently the intraocular pressure with time starts to return to pathological levels. Usually the scarring occurs several months Lo yews after surgery, and the use of antimitotic agents such as 5-fluorouracil and Mitomycin C during surgery improves the surgical results. However, Mitomycin C and 5-fluorouracil are very toxic compounds with a narrow therapeutic index, and difficult to use clinically. Late complications such as conjunctival holes may ensue after the use of e.g. Mitomycin C. Thus there is a need for better and safer drugs to be used as a complement to the surgical procedure to prevent the scarring of the filtration system created by surgery.
The above problems associated with glaucoma surgery are now solved by the present invention as defined in the attached claims, hereby incorporated by reference. The invention is based on the unexpected finding that prostaglandins of type A and J may be highly effective in preventing scar formation that typically occurs after glaucoma surgery, and that the compositions comprising these compounds and the methods described have advantages over the compositions and methods hitherto known.